Aging is a chronic process causing degeneration of cells, tissues, and organs, including choroidal blood vessels, retinal pigment epithelium cells (RPEC) and Bruch's membrane of the eye. Arteriosclerotic aging changes choroidal blood vessels, particularly the macular chorio-capillaris resulting in a decrease in total capillary blood flow. As a result, retinal pigment epithelium starts to accumulate drusen and lipofuscin, alters cell shape, density, pigmentation, lysosomal activity and extracellular matrix formation. Gradually, Bruch's membrane shows thickening and decreased permeability, resulting in breakdown that can allow choroidal neovascularization (CNV) to appear, which ultimately results in neovascular age-related macular degeneration (also wet age-related macular degeneration) and blindness. Clinical evidence has suggested that ischemia or decreases in choroidal blood flow may be associated with a number of serious retinal diseases, including age-related macular degeneration (AMD or ARMD) (Grunwald et al., 1998, Invest Ophthalmol Vis Sci., 39(2):385-390; Grunwald et al., 2005, Invest Ophthalmol Vis Sci., 46(3):1033-1038; Ciulla et al., 1999, Am J. Ophthalmol, 128(1):75-80; Metelitsina et al., 2006, Br J Ophthalmol, 90(3):342-346; Metelitsina et al., 2008, Invest Ophthalmol Vis Sci, 49(1):358-363). Both ocular and systemic vascular factors, such as systemic hypertension and ocular hypertension, are thought to play a role in the development of AMD and in choroidal neovascularization (Metelitsina 2006; Metelitsina 2008; U.S. Pat. No. 5,500,230 to Nathanson et al.). Thus, there is a need to identity agents that prevent choroidal neovascularization and/or increase choroidal blood flow.
Numerous methods have been attempted to treat age-related macular degeneration without success. They include laser photocoagulation for choroidal neovascularization, radiation treatment, transpupillary thermotherapy of subfoveal occult choroidal neovascularization, submacular surgery, limited macular translocation, adjuncts in surgery, argon laser to drusen, infrared diode laser photocoagulation for treatment of wet AMD. Recently, compositions for treating the non-neovascular or dry AMD comprising hypotensive agents, such as hydralazine, were described in U.S. Pat. No. 8,088,773 to Chiou, which is incorporated by reference herein.
The foregoing examples of the related art and limitations related therewith are intended to be illustrative and not exclusive. Other limitations of the related art will become apparent to those of skill in the art upon a reading of the specification and a study of the drawings.